title: Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis.
abstract: Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability.
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon [2] CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon [3] Centre Léon Bérard [4] Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Wiel
authors.forename: A
authors.initials: A
authors.lastname: Augert
authors.forename: D F
authors.initials: DF
authors.lastname: Vincent
authors.forename: D
authors.initials: D
authors.lastname: Gitenay
authors.forename: D
authors.initials: D
authors.lastname: Vindrieux
authors.forename: B
authors.initials: B
authors.lastname: Le Calvé
authors.forename: V
authors.initials: V
authors.lastname: Arfi
authors.forename: H
authors.initials: H
authors.lastname: Lallet-Daher
authors.forename: C
authors.initials: C
authors.lastname: Reynaud
authors.forename: I
authors.initials: I
authors.lastname: Treilleux
authors.forename: L
authors.initials: L
authors.lastname: Bartholin
authors.forename: E
authors.initials: E
authors.lastname: Lelievre
authors.forename: D
authors.initials: D
authors.lastname: Bernard
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D008249:Protein-Lysine 6-Oxidase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases